Augmenting CAR T-cell Functions with LIGHT

Area of Science:

• Immunology
• Oncology
• Cell Therapy

Background:

• Chimeric antigen receptor (CAR) T-cell therapy is effective against B-cell cancers but faces challenges in solid tumors due to target antigen heterogeneity.
• Antigen escape and relapse remain significant hurdles for CAR T-cell therapy in solid tumor treatment.

Purpose of the Study:

• To develop a novel CAR T-cell strategy to overcome antigen heterogeneity in solid tumors.
• To enhance CAR T-cell efficacy by incorporating LIGHT-mediated, antigen-independent tumor cell killing.

Main Methods:

• Engineered CAR T cells to overexpress LIGHT, a ligand interacting with lymphotoxin-β receptor (LTBR) on cancer cells and herpes virus entry mediator (HVEM) on immune cells.
• Assessed the dual-mechanism cytotoxicity (CAR-mediated and LIGHT-mediated) and immunostimulatory properties of engineered CAR T cells.

Main Results:

• LIGHT-expressing CAR T cells demonstrated both CAR-dependent, antigen-specific killing and LIGHT-dependent, antigen-independent cytotoxicity against tumor cells.
• Enhanced proliferation and improved cytolytic profile were observed in CAR T cells engineered to express LIGHT.
• The dual-acting CAR T cells showed potential to eliminate antigen-negative tumor cells, addressing a key cause of relapse.

Conclusions:

• LIGHT-expressing CAR T cells offer a promising strategy to overcome antigen heterogeneity in solid tumors.
• This approach enhances CAR T-cell persistence and efficacy, potentially preventing disease relapse.
• LIGHT-engineered CAR T cells represent a potential advancement in solid tumor immunotherapy.